This project delineates biochemical and pharmacological properties of sigma receptors and ligands. The interaction between neurosteroids and sigma-1 receptors may be of therapeutic interest during physiological or pathological aging, particularly concerning their modulatory role on cognitive functions. To measure the contribution of endogenous neurosteroid levels to the antiamnesic effects of sigma-1 agonists, we examine this year the effects of key enzymes involved in neurosteroid synthesis, in adrenalectomized/castrated (AdX/CX) mice to avoid the effect of circulating steroids. We used trilostane and finasteride respectively to decrease and increase the progesterone level. Results indicate that the available sigma-1 receptor binding sites are increased by trilostane and decreased by finasteride. The antiamnesic effects of sigma-1 agonist PRE-084 is facilitated in AdX/CX mice and even more after trilostane treatment. The PRE-084 effect is blocked by finasteride. These results confirm that endogenous neurosteroidal levels modulate sigma-1 receptor-mediated learning and memory processes and reveal that, among neurosteroids, progesterone may be the main modulator of sigma-1 receptors. - sigma receptor; learning and memory; neurosteroid; calcium signaling.